The development and spread of bacterial antibiotic resistance has emerged as a major public health concern. Pathogenic bacteria once easily controlled by antimicrobial drugs now frequently fail to respond to most antibiotics. Most research on the causes and consequences of antibiotic resistance focuses on clinical isolates of pathogenic bacteria, i.e. isolates from infected humans in hospitals. These studies reveal the diversity of resistance mechanisms and genes, the genetic details of how resistance spreads between bacterial lineages and provide estimates of the speed with which such spread occurs in hospital settings. Such clinically based studies play an essential role in efforts to track the course of antibiotic resistance evolution and suggest the priority of drug use for particular pathogens. However, these studies suffer from two critical omissions. First, R genes characterized from clinical isolates represent a small fraction of the existing diversity of R genes. It is now clear that antibiotic resistance predates the human mediated use of antibiotics and it is equally clear that for every drug humans discover, design or develop, it is almost certainly the case that microbes already possess a defensive mechanism and it is only a matter of time before that mechanism is transferred to a human pathogen. It is critical to have a more complete understanding of the diversity of existing resistance mechanisms if we are to successfully plan antimicrobial strategies. Second, these studies ignore the complex ecological and evolutionary pressures that bacteria and their resistance genes experience in nature (in addition to those resulting from human-mediated antibiotic use). This information is critical to the development of rational treatment therapies. The goal of this research is to explore and contrast the evolution of antibiotic resistance in natural and clinical populations of enteric bacteria and to apply these data to efforts aimed at the development of more effective antibiotic therapies. We propose here the first "comprehensive" survey of antibiotic resistance evolution in natural populations of bacteria. What makes our study comprehensive is the combined focus on antibiotic resistance phenotypes, genotypes, levels of genetic variation and divergence, estimates of resistance-associated fitness effects and the use of these data to inform existing antibiotic therapies and contribute to the design of more rational or novel therapies.